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Cancer Cell. 2016 Oct 10;30(4):637-650. doi: 10.1016/j.ccell.2016.09.002.

Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer.

Author information

1
Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
2
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
3
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
4
Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA.
5
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
6
Stevenson University, Stevenson, MD 21153, USA.
7
Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
8
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA; Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
9
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA; Van Andel Research Institute, Grand Rapids, MI 49503.
10
Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA. Electronic address: frassool@som.umaryland.edu.

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.

KEYWORDS:

AML; DNA damage; DNA double-strand break; DNA repair; DNMT inhibitor; DNMT1; PARP; PARP inhibitor; PARP trapping; breast cancer

Comment in

PMID:
27728808
PMCID:
PMC5201166
DOI:
10.1016/j.ccell.2016.09.002
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

DISCLOSURES C.R., F.V.R. and S.B.B. share co-inventor ship on US Provisional Patent Application Number: 61/929,680 for the concept of the combinatorial therapy.

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